Mission Statement

As part of the federal government’s National Institutes of Health (NIH), the National Eye Institute’s mission is to “conduct and support research, training, health information dissemination, and other programs with respect to blinding eye diseases, visual disorders, mechanisms of visual function, preservation of sight, and the special health problems and requirements of the blind.”

Research Interests

The major goal of the Ocular Gene Therapy Core (OGTC) is to develop adeno-associated virus (AAV)-based gene therapeutics for inherited and acquired ocular diseases. We also provide expertise and cutting edge design options of AAV vectors to collaborating research groups interested in bringing AAV vector-based gene therapeutics to the clinic.

AAV vector is one of the most efficient gene delivery tools for modifying retinal cells. Gene therapy clinical trials using AAV vectors have been conducted for treatment of several inherited retinal diseases (IRD) and have shown promising results in patients with Leber congenital amaurosis type 2 (LCA2), choroideremia and Leber's hereditary optic neuropathy (LHON). To date, over 250 genes have been identified as disease-causing genes for IRD, and a majority of these diseases could be targets of gene therapy. We have been focusing our efforts on developing therapies for the diseases affecting relatively large patient populations or with severe symptoms.

Research Summary

Active Areas of Current Research

1. Gene replacement therapy for X-Linked Retinitis Pigmentosa (XLRP)

Mutations in Retinitis Pigmentosa GTPase Regulator (RPGR) and Retinitis Pigmentosa 2 (RP2) genes account for the majority of XLRP. RPGR mutations are one of the most frequent causes of total RP cases. We have conducted long-term efficacy and preliminary safety studies of gene replacement therapy in Rpgr and Rp2 gene knock-out mouse models (Wu et al., Hum Mol Genet, 2015; Mookherjee, et al., Hum Mol Genet, 2015), which have paved the way for further clinical development. NEI is prosecuting patent on this technology.

2. Mechanism-based gene therapy for LCA due to CEP290 mutations

Mutations in CEP290 gene are the most common cause of LCA. Gene replacement for CEP290-LCA is difficult to achieve, since a full-length CEP290 coding sequence is too large to be delivered by an AAV vector. We are currently seeking mechanism-based gene therapy for the disease, based on the existing knowledge of CEP290 protein structure and its interactome.

3. CRISPR/Cas9 mediated genome editing in postmitotic retinal neurons

We have established an AAV-based photoreceptor-specific CRISPR/Cas9 genome editing system. As precise gene correction or modification relies on homology-directed repair which is unfavorable in postmitotic photoreceptors, our initial effort will be focused on gene disruption mediated by non-homologous end joining. This may lead to novel therapies for retinal degeneration caused by gain-of-function or dominant mutations.

We have been actively engaged in the pre-clinical and clinical development of gene therapy for X-linked Juvenile Retinoschisis (XLRS) led by Dr. Paul Sieving (NEI Director). We helped to design and develop the human retinoschisin AAV vector, which is currently being tested in phase I clinical trials of XLRS at NEI (https://clinicaltrials.gov/ct2/show/NCT02317887). NEI is also prosecuting patent on this technology.